HHS Public Access Author manuscript Author Manuscript
Clin Cancer Res. Author manuscript; available in PMC 2017 May 15. Published in final edited form as: Clin Cancer Res. 2016 November 15; 22(22): 5461–5471. doi:10.1158/1078-0432.CCR-15-2839.
Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma
Author Manuscript
Toni K. Choueiri1, Mayer N. Fishman2, Bernard Escudier3, David F. McDermott4, Charles G. Drake5, Harriet Kluger6, Walter M. Stadler7, Jose Luis Perez-Gracia8, Douglas G. McNeel9, Brendan Curti10, Michael R. Harrison11, Elizabeth R. Plimack12, Leonard Appleman13, Lawrence Fong14, Laurence Albiges15, Lewis Cohen16, Tina C. Young16, Scott D. Chasalow16, Petra Ross-Macdonald16, Shivani Srivastava16, Maria Jure-Kunkel16, John F. Kurland16, Jason S. Simon16, and Mario Sznol6 1Kidney
Author Manuscript
Cancer Center, Dana-Farber Cancer Institute Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts 2Moffitt Cancer Center, Tampa, Florida 3Institut Gustave Roussy, Villejuif, France 4Beth Israel Deaconess Medical Center, Boston, Massachusetts 5Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and the Brady Urological Institute, Baltimore, Maryland 6Yale University School of Medicine and Yale Cancer Center, New Haven, Connecticut 7University of Chicago School of Medicine, Chicago, Illinois 8Clinica Universidad de Navarra, Pamplona, Navarra, Spain 9University of Wisconsin at Carbone Cancer Center, Madison, Wisconsin 10Earle A. Chiles Research Institute, Portland, Oregon 11Duke University Medical Center, Durham, North Carolina 12Fox Chase Cancer Center, Philadelphia, Pennsylvania 13University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 14University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California 15Kidney Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts, and Institut Gustave Roussy, Villejuif, France 16Bristol-Myers Squibb, Princeton, New Jersey
Abstract Purpose—Nivolumab, an anti-PD-1 immune checkpoint inhibitor, improved overall survival versus everolimus in a phase 3 trial of previously treated patients with metastatic renal cell carcinoma (mRCC). We investigated immunomodulatory activity of nivolumab in a hypothesisgenerating prospective mRCC trial.
Author Manuscript
Experimental Design—Nivolumab was administered intravenously every 3 weeks at 0.3, 2, or 10 mg/kg to previously treated patients and 10 mg/kg to treatment-naïve patients with mRCC. Baseline and on-treatment biopsies and blood were obtained. Clinical activity, tumor-associated
Corresponding Author: Toni K. Choueiri, MD, Dana-Farber Cancer Institute, 450 Brookline Avenue (DANA 1230), Boston, MA 02115. Phone: 617-632-5456, Fax: 617-632-2165. [email protected]. J.F. Kurland and J.S. Simon were employees of Bristol-Myers Squibb at the time the study was conducted and data analyzed. Prior presentation: This work has been presented in part at the American Society of Clinical Oncology Annual Meeting, Chicago, IL, May 30 – June 3, 2014 (abstract #5012), the European Society for Medical Oncology Congress, Madrid, Spain, September 26–30, 2014 (abstract #1051PD), the American Association of Cancer Research, Philadelphia, Pennsylvania, April 18–22, 2015 (abstract #1306), and the American Society of Clinical Oncology Annual Meeting, Chicago, IL, May 29 –June 2, 2015 (abstract #4500). ClinicalTrials.gov Identifier: NCT01358721
Choueiri et al.
Page 2
Author Manuscript
lymphocytes, PD-L1 expression (Dako immunohistochemistry; ≥5% vs. 1.3 fold, P < 0.01) that are specifically associated with either the lymphoid or myeloid immune lineage. Within the lymphoid lineage, the 10 transcripts indicated are specific to T cells. Data are included from the 42 patients with measures at both time points, separated by their previous treatment status. Genes labeled in orange are members of interferon-regulated transcription modules collated by the BRi2 consortium (34). Markers of immune cytolytic activity are labeled in green. B. Change of 30 transcripts in peripheral blood associated with immune lineages and
Clin Cancer Res. Author manuscript; available in PMC 2017 May 15.
Choueiri et al.
Page 19
Author Manuscript
significantly regulated (≥1.2-fold, P < 0.01) in all treatment groups at cycle 1 day 2. Data are included from the 70 patients with measures at both time points, separated by treatment group. Genes labeled in orange are members of interferon-regulated transcription modules collated by the BRi2 consortium (34).
Author Manuscript Author Manuscript Author Manuscript Clin Cancer Res. Author manuscript; available in PMC 2017 May 15.
Choueiri et al.
Page 20
Author Manuscript Author Manuscript Author Manuscript Figure 3.
Author Manuscript
Effect of nivolumab on chemokine markers. A. Fold change from baseline at cycle 2 day 8 vs. baseline in serum concentrations of CXCL9 and CXCL10 in all treatment groups (N = 83). Both axes are on the log base-2 scale. B. Scatter plot matrix of fold changes from baseline (log base-2 scale) in CXCL9 and CXCL10 among 83 patients who had serum data at baseline and C2D8. The diagonal panels give kernel density estimates and histograms summarizing the univariate distributions of CXCL9 and CXCL10 individually. C. Gene expression levels for CXCL9 (4283_at) and CXCL10 (3627_at) in fresh tumor tissue samples. Values presented are least squares means of the (log-2) robust multi-array intensity
Clin Cancer Res. Author manuscript; available in PMC 2017 May 15.
Choueiri et al.
Page 21
Author Manuscript
for the treatment group and time point indicated. Error bars indicate 95% confidence intervals estimated from the extended linear model. D. Gene expression levels for CXCL9 (4283_at) and CXCL10 (3627_at) in biopsies obtained at cycle 2 day 8 versus serum concentrations of CXCL9 and CXCL10 in the same patient at cycle 2 day 8 (N = 54). Both axes are on the log base-2 scale. Shaded area represents 95% confidence interval estimated from a linear model.
Author Manuscript Author Manuscript Author Manuscript Clin Cancer Res. Author manuscript; available in PMC 2017 May 15.
Choueiri et al.
Page 22
Table 1
Author Manuscript
Baseline patient characteristics and demographics Previously Treated, Nivolumab 0.3, 2, and 10 mg/kg (N = 67)
Treatment-naïve, Nivolumab 10 mg/kg (N = 24)
Total (N = 91)
61.0
63.5
61.0
Male
46 (69)
15 (63)
61 (67)
Female
21 (31)
9 (38)
30 (33)
Surgery
64 (96)
23 (96)
87 (96)
Radiotherapy
25 (37)
5 (21)
30 (33)
67 (100)
0
67 (74)
60 (90)
0
60 (66)
Adjuvant therapy
5 (7)
0
5 (6)
Neoadjuvant therapy
5 (7)
0
5 (6)
Median age, years Sex, n (%)
Previous therapy, n (%)
Previous systemic therapy
Author Manuscript
Therapy for metastatic disease
Author Manuscript Author Manuscript Clin Cancer Res. Author manuscript; available in PMC 2017 May 15.
Author Manuscript 9 (41) 3 (14)
Stable disease
Progressive disease
Unable to determine
NE
At 48 weeks
NR
61 (36, 78)
72 (48, 86)
NE
44 (23, 63)
3 (14)
5 (23)
10 (46)
4 (18)
0
5.2, 40.3
4 (18)
Nivolumab 2 mg/kg (N = 22)
Previously Treated (N = 67)
Clin Cancer Res. Author manuscript; available in PMC 2017 May 15.
Confirmed response only.
All treated patients were evaluated for response.
b
a
25.2 (12.0, NR)
51 (27, 71)
74 (48, 88)
32 (13, 52)
58 (35, 76)
1 (4)
6 (26)
11 (48)
5 (22)
0
7.5, 43.7
5 (22)
Nivolumab 10 mg/kg (N = 23)
Abbreviations: CI, confidence interval; CR, complete response; NE, not evaluated; NR, not reached; PR, partial response.
16.4 (10.1, NR)
44 (22, 64)
At 24 months
Median overall survival, months (95% CI)
71 (47, 86)
At 12 months
Overall survival rate, % (95% CI)
NE
At 24 weeks
Progression-free survival rate, % (95% CI)
2 (9) 8 (36)
PR
0
1.1, 29.2
2 (9)
CR
Best response, n (%)
95% CI
Objective response rate, n (%)b
Author Manuscript Nivolumab 0.3 mg/kg (N = 22)
Author Manuscript
Clinical activity
NR
76 (51, 89)
81 (57, 92)
39 (18, 59)
50 (28, 68)
1 (4)
7 (29)
13 (54)
1 (4)
2 (8)
2.7, 32.4
3 (13)
Nivolumab 10 mg/kg (N = 24)
Treatment-naïve
–
58 (46, 68)
75 (64, 83)
25 (16, 35)
43 (32, 53)
8 (9)
27 (30)
42 (46)
12 (13)
2 (2)
8.7, 24.5
14 (15)
Total (N = 91)a
Author Manuscript
Table 2 Choueiri et al. Page 23
Author Manuscript 22 (100)
15 (68)
Grade 3/4
8 (36) 7 (32) 7 (32) 4 (18)
Nausea
Constipation
Cough
Diarrhea
0
0
1 (5)
0
0
Clin Cancer Res. Author manuscript; available in PMC 2017 May 15. 0
Colitis
2 (9) 1 (5)
Acute renal failure
3 (14)
Blood creatinine increased
Renal
0
2 (9)
ALT increased
Blood bilirubin increased
1 (5)
AST increased
3 (14)
4 (18)
Diarrhea
Hepatic
4 (18)
Gastrointestinal
0
Palmar-plantar erythrodysesthesia
1 (5)
Rash pruritic 0
5 (23)
Urticaria
3 (14)
Rash
9 (41)
Pruritus
Skin
1 (5)
0
2 (9)
0
1 (5)
1 (5)
2 (9)
0
0
0
0
0
0
0
0
0
Previously Treated
1 (5)
4 (18)
4 (18)
0
0
0
3 (14)
0
4 (18)
4 (18)
0
0
0
2 (9)
4 (18)
5 (23)
4 (18)
8 (36)
6 (27)
7 (32)
13 (59)
22 (100)
Any Grade
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1 (5)
0
2 (9)
8 (36)
Grade 3/4
Nivolumab 2 mg/kg (N = 22)
Select AEs (occurring in ≥2 patients in any treatment group for preferred term)
12 (55)
Fatigue
Occurring in ≥15% of patients in all treatment groups (any grade)
Total
Any Grade
Nivolumab 0.3 mg/kg (N = 22)
Author Manuscript
Event, n (%)
2 (9)
2 (9)
3 (13)
2 (9)
2 (9)
3 (13)
5 (22)
2 (9)
5 (22)
6 (26)
0
2 (9)
2 (9)
2 (9)
4 (17)
9 (39)
5 (22)
4 (17)
4 (17)
6 (26)
15 (65)
23 (100)
Any Grade
1 (4)
0
1 (4)
1 (4)
1 (4)
2 (9)
3 (13)
1 (4)
1 (4)
2 (9)
0
0
0
0
0
1 (4)
1 (4)
0
0
0
0
13 (57)
Grade 3/4
Nivolumab 10 mg/kg (N = 23)
Author Manuscript
Treatment-related adverse events
0
2 (8)
2 (8)
2 (8)
2 (8)
2 (8)
2 (8)
2 (8)
9 (38)
9 (38)
2 (8)
1 (4)
1 (4)
2 (8)
4 (17)
10 (42)
9 (38)
5 (21)
6 (25)
10 (42)
13 (54)
24 (100)
Any Grade
0
0
0
0
0
0
0
2 (8)
1 (4)
3 (13)
0
0
0
0
0
1 (4)
0
0
0
1 (4)
12 (50)
Grade 3/4
Nivolumab 10 mg/kg (N = 24)
Treatment-naïve
Author Manuscript
Table 3 Choueiri et al. Page 24
1 (5)
Infusion-related reaction
0
0
1 (5)
1 (5)
0
0
Grade 3/4
1 (5)
2 (9)
0
0
1 (5)
3 (14)
Any Grade
0
0
0
0
0
0
Grade 3/4
Nivolumab 2 mg/kg (N = 22)
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
1 (5)
1 (5)
1 (5)
1 (5)
1 (5)
Any Grade
Hypersensitivity/infusion reaction
Pneumonitis
Pulmonary
Hypothyroidism
Endocrine
Author Manuscript Nivolumab 0.3 mg/kg (N = 22)
Author Manuscript
Event, n (%)
4 (17)
5 (22)
2 (9)
2 (9)
3 (13)
4 (17)
Any Grade
0
0
1 (4)
1 (4)
0
0
Grade 3/4
Nivolumab 10 mg/kg (N = 23)
5 (21)
6 (25)
3 (13)
3 (13)
2 (8)
3 (13)
Any Grade
1 (4)
1 (4)
0
0
0
1 (4)
Grade 3/4
Nivolumab 10 mg/kg (N = 24)
Treatment-naïve
Author Manuscript
Previously Treated
Choueiri et al. Page 25
Author Manuscript
Clin Cancer Res. Author manuscript; available in PMC 2017 May 15.
Clin Cancer Res. Author manuscript; available in PMC 2017 May 15. Published in final edited form as: Clin Cancer Res. 2016 November 15; 22(22): 5461–5471. doi:10.1158/1078-0432.CCR-15-2839.
Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma
Author Manuscript
Toni K. Choueiri1, Mayer N. Fishman2, Bernard Escudier3, David F. McDermott4, Charles G. Drake5, Harriet Kluger6, Walter M. Stadler7, Jose Luis Perez-Gracia8, Douglas G. McNeel9, Brendan Curti10, Michael R. Harrison11, Elizabeth R. Plimack12, Leonard Appleman13, Lawrence Fong14, Laurence Albiges15, Lewis Cohen16, Tina C. Young16, Scott D. Chasalow16, Petra Ross-Macdonald16, Shivani Srivastava16, Maria Jure-Kunkel16, John F. Kurland16, Jason S. Simon16, and Mario Sznol6 1Kidney
Author Manuscript
Cancer Center, Dana-Farber Cancer Institute Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts 2Moffitt Cancer Center, Tampa, Florida 3Institut Gustave Roussy, Villejuif, France 4Beth Israel Deaconess Medical Center, Boston, Massachusetts 5Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and the Brady Urological Institute, Baltimore, Maryland 6Yale University School of Medicine and Yale Cancer Center, New Haven, Connecticut 7University of Chicago School of Medicine, Chicago, Illinois 8Clinica Universidad de Navarra, Pamplona, Navarra, Spain 9University of Wisconsin at Carbone Cancer Center, Madison, Wisconsin 10Earle A. Chiles Research Institute, Portland, Oregon 11Duke University Medical Center, Durham, North Carolina 12Fox Chase Cancer Center, Philadelphia, Pennsylvania 13University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 14University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California 15Kidney Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts, and Institut Gustave Roussy, Villejuif, France 16Bristol-Myers Squibb, Princeton, New Jersey
Abstract Purpose—Nivolumab, an anti-PD-1 immune checkpoint inhibitor, improved overall survival versus everolimus in a phase 3 trial of previously treated patients with metastatic renal cell carcinoma (mRCC). We investigated immunomodulatory activity of nivolumab in a hypothesisgenerating prospective mRCC trial.
Author Manuscript
Experimental Design—Nivolumab was administered intravenously every 3 weeks at 0.3, 2, or 10 mg/kg to previously treated patients and 10 mg/kg to treatment-naïve patients with mRCC. Baseline and on-treatment biopsies and blood were obtained. Clinical activity, tumor-associated
Corresponding Author: Toni K. Choueiri, MD, Dana-Farber Cancer Institute, 450 Brookline Avenue (DANA 1230), Boston, MA 02115. Phone: 617-632-5456, Fax: 617-632-2165. [email protected]. J.F. Kurland and J.S. Simon were employees of Bristol-Myers Squibb at the time the study was conducted and data analyzed. Prior presentation: This work has been presented in part at the American Society of Clinical Oncology Annual Meeting, Chicago, IL, May 30 – June 3, 2014 (abstract #5012), the European Society for Medical Oncology Congress, Madrid, Spain, September 26–30, 2014 (abstract #1051PD), the American Association of Cancer Research, Philadelphia, Pennsylvania, April 18–22, 2015 (abstract #1306), and the American Society of Clinical Oncology Annual Meeting, Chicago, IL, May 29 –June 2, 2015 (abstract #4500). ClinicalTrials.gov Identifier: NCT01358721
Choueiri et al.
Page 2
Author Manuscript
lymphocytes, PD-L1 expression (Dako immunohistochemistry; ≥5% vs. 1.3 fold, P < 0.01) that are specifically associated with either the lymphoid or myeloid immune lineage. Within the lymphoid lineage, the 10 transcripts indicated are specific to T cells. Data are included from the 42 patients with measures at both time points, separated by their previous treatment status. Genes labeled in orange are members of interferon-regulated transcription modules collated by the BRi2 consortium (34). Markers of immune cytolytic activity are labeled in green. B. Change of 30 transcripts in peripheral blood associated with immune lineages and
Clin Cancer Res. Author manuscript; available in PMC 2017 May 15.
Choueiri et al.
Page 19
Author Manuscript
significantly regulated (≥1.2-fold, P < 0.01) in all treatment groups at cycle 1 day 2. Data are included from the 70 patients with measures at both time points, separated by treatment group. Genes labeled in orange are members of interferon-regulated transcription modules collated by the BRi2 consortium (34).
Author Manuscript Author Manuscript Author Manuscript Clin Cancer Res. Author manuscript; available in PMC 2017 May 15.
Choueiri et al.
Page 20
Author Manuscript Author Manuscript Author Manuscript Figure 3.
Author Manuscript
Effect of nivolumab on chemokine markers. A. Fold change from baseline at cycle 2 day 8 vs. baseline in serum concentrations of CXCL9 and CXCL10 in all treatment groups (N = 83). Both axes are on the log base-2 scale. B. Scatter plot matrix of fold changes from baseline (log base-2 scale) in CXCL9 and CXCL10 among 83 patients who had serum data at baseline and C2D8. The diagonal panels give kernel density estimates and histograms summarizing the univariate distributions of CXCL9 and CXCL10 individually. C. Gene expression levels for CXCL9 (4283_at) and CXCL10 (3627_at) in fresh tumor tissue samples. Values presented are least squares means of the (log-2) robust multi-array intensity
Clin Cancer Res. Author manuscript; available in PMC 2017 May 15.
Choueiri et al.
Page 21
Author Manuscript
for the treatment group and time point indicated. Error bars indicate 95% confidence intervals estimated from the extended linear model. D. Gene expression levels for CXCL9 (4283_at) and CXCL10 (3627_at) in biopsies obtained at cycle 2 day 8 versus serum concentrations of CXCL9 and CXCL10 in the same patient at cycle 2 day 8 (N = 54). Both axes are on the log base-2 scale. Shaded area represents 95% confidence interval estimated from a linear model.
Author Manuscript Author Manuscript Author Manuscript Clin Cancer Res. Author manuscript; available in PMC 2017 May 15.
Choueiri et al.
Page 22
Table 1
Author Manuscript
Baseline patient characteristics and demographics Previously Treated, Nivolumab 0.3, 2, and 10 mg/kg (N = 67)
Treatment-naïve, Nivolumab 10 mg/kg (N = 24)
Total (N = 91)
61.0
63.5
61.0
Male
46 (69)
15 (63)
61 (67)
Female
21 (31)
9 (38)
30 (33)
Surgery
64 (96)
23 (96)
87 (96)
Radiotherapy
25 (37)
5 (21)
30 (33)
67 (100)
0
67 (74)
60 (90)
0
60 (66)
Adjuvant therapy
5 (7)
0
5 (6)
Neoadjuvant therapy
5 (7)
0
5 (6)
Median age, years Sex, n (%)
Previous therapy, n (%)
Previous systemic therapy
Author Manuscript
Therapy for metastatic disease
Author Manuscript Author Manuscript Clin Cancer Res. Author manuscript; available in PMC 2017 May 15.
Author Manuscript 9 (41) 3 (14)
Stable disease
Progressive disease
Unable to determine
NE
At 48 weeks
NR
61 (36, 78)
72 (48, 86)
NE
44 (23, 63)
3 (14)
5 (23)
10 (46)
4 (18)
0
5.2, 40.3
4 (18)
Nivolumab 2 mg/kg (N = 22)
Previously Treated (N = 67)
Clin Cancer Res. Author manuscript; available in PMC 2017 May 15.
Confirmed response only.
All treated patients were evaluated for response.
b
a
25.2 (12.0, NR)
51 (27, 71)
74 (48, 88)
32 (13, 52)
58 (35, 76)
1 (4)
6 (26)
11 (48)
5 (22)
0
7.5, 43.7
5 (22)
Nivolumab 10 mg/kg (N = 23)
Abbreviations: CI, confidence interval; CR, complete response; NE, not evaluated; NR, not reached; PR, partial response.
16.4 (10.1, NR)
44 (22, 64)
At 24 months
Median overall survival, months (95% CI)
71 (47, 86)
At 12 months
Overall survival rate, % (95% CI)
NE
At 24 weeks
Progression-free survival rate, % (95% CI)
2 (9) 8 (36)
PR
0
1.1, 29.2
2 (9)
CR
Best response, n (%)
95% CI
Objective response rate, n (%)b
Author Manuscript Nivolumab 0.3 mg/kg (N = 22)
Author Manuscript
Clinical activity
NR
76 (51, 89)
81 (57, 92)
39 (18, 59)
50 (28, 68)
1 (4)
7 (29)
13 (54)
1 (4)
2 (8)
2.7, 32.4
3 (13)
Nivolumab 10 mg/kg (N = 24)
Treatment-naïve
–
58 (46, 68)
75 (64, 83)
25 (16, 35)
43 (32, 53)
8 (9)
27 (30)
42 (46)
12 (13)
2 (2)
8.7, 24.5
14 (15)
Total (N = 91)a
Author Manuscript
Table 2 Choueiri et al. Page 23
Author Manuscript 22 (100)
15 (68)
Grade 3/4
8 (36) 7 (32) 7 (32) 4 (18)
Nausea
Constipation
Cough
Diarrhea
0
0
1 (5)
0
0
Clin Cancer Res. Author manuscript; available in PMC 2017 May 15. 0
Colitis
2 (9) 1 (5)
Acute renal failure
3 (14)
Blood creatinine increased
Renal
0
2 (9)
ALT increased
Blood bilirubin increased
1 (5)
AST increased
3 (14)
4 (18)
Diarrhea
Hepatic
4 (18)
Gastrointestinal
0
Palmar-plantar erythrodysesthesia
1 (5)
Rash pruritic 0
5 (23)
Urticaria
3 (14)
Rash
9 (41)
Pruritus
Skin
1 (5)
0
2 (9)
0
1 (5)
1 (5)
2 (9)
0
0
0
0
0
0
0
0
0
Previously Treated
1 (5)
4 (18)
4 (18)
0
0
0
3 (14)
0
4 (18)
4 (18)
0
0
0
2 (9)
4 (18)
5 (23)
4 (18)
8 (36)
6 (27)
7 (32)
13 (59)
22 (100)
Any Grade
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1 (5)
0
2 (9)
8 (36)
Grade 3/4
Nivolumab 2 mg/kg (N = 22)
Select AEs (occurring in ≥2 patients in any treatment group for preferred term)
12 (55)
Fatigue
Occurring in ≥15% of patients in all treatment groups (any grade)
Total
Any Grade
Nivolumab 0.3 mg/kg (N = 22)
Author Manuscript
Event, n (%)
2 (9)
2 (9)
3 (13)
2 (9)
2 (9)
3 (13)
5 (22)
2 (9)
5 (22)
6 (26)
0
2 (9)
2 (9)
2 (9)
4 (17)
9 (39)
5 (22)
4 (17)
4 (17)
6 (26)
15 (65)
23 (100)
Any Grade
1 (4)
0
1 (4)
1 (4)
1 (4)
2 (9)
3 (13)
1 (4)
1 (4)
2 (9)
0
0
0
0
0
1 (4)
1 (4)
0
0
0
0
13 (57)
Grade 3/4
Nivolumab 10 mg/kg (N = 23)
Author Manuscript
Treatment-related adverse events
0
2 (8)
2 (8)
2 (8)
2 (8)
2 (8)
2 (8)
2 (8)
9 (38)
9 (38)
2 (8)
1 (4)
1 (4)
2 (8)
4 (17)
10 (42)
9 (38)
5 (21)
6 (25)
10 (42)
13 (54)
24 (100)
Any Grade
0
0
0
0
0
0
0
2 (8)
1 (4)
3 (13)
0
0
0
0
0
1 (4)
0
0
0
1 (4)
12 (50)
Grade 3/4
Nivolumab 10 mg/kg (N = 24)
Treatment-naïve
Author Manuscript
Table 3 Choueiri et al. Page 24
1 (5)
Infusion-related reaction
0
0
1 (5)
1 (5)
0
0
Grade 3/4
1 (5)
2 (9)
0
0
1 (5)
3 (14)
Any Grade
0
0
0
0
0
0
Grade 3/4
Nivolumab 2 mg/kg (N = 22)
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
1 (5)
1 (5)
1 (5)
1 (5)
1 (5)
Any Grade
Hypersensitivity/infusion reaction
Pneumonitis
Pulmonary
Hypothyroidism
Endocrine
Author Manuscript Nivolumab 0.3 mg/kg (N = 22)
Author Manuscript
Event, n (%)
4 (17)
5 (22)
2 (9)
2 (9)
3 (13)
4 (17)
Any Grade
0
0
1 (4)
1 (4)
0
0
Grade 3/4
Nivolumab 10 mg/kg (N = 23)
5 (21)
6 (25)
3 (13)
3 (13)
2 (8)
3 (13)
Any Grade
1 (4)
1 (4)
0
0
0
1 (4)
Grade 3/4
Nivolumab 10 mg/kg (N = 24)
Treatment-naïve
Author Manuscript
Previously Treated
Choueiri et al. Page 25
Author Manuscript
Clin Cancer Res. Author manuscript; available in PMC 2017 May 15.
